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Discussion of Staff Draft Report on Research Involving Persons with Mental Disorders Affecting Decision Making Capacity: James Childress, Ph.D., Jonathan Moreno, Ph.D., and Commissioners

DR. CHILDRESS: [Request for names to add to list of readers of Commission draft report on research involving persons with mental disorders affecting decision making capacity - inaudible]

DR. MESLIN: We have the staff up and letters going out.

DR. CHILDRESS: Okay. Are there any questions for Eric on that topic?

Itís presumably the sort of thing that we could incorporate results not only into a staff draft but even into a Commission draft, if we reach that point in our deliberations during this session.

You have on the first page of the memorandum several general items. Be sure to mention that to staff so that we can make sure we get the appropriate materials. The flowchart thatís mentioned has now been updated and made, what shall we say, more complicated.

DR. CHILDRESS: I havenít had a chance to look at it yet. But we can come to that in the course of the discussion. Jonathan and staff have prepared that and we also have it available on an overhead so we can walk through that as need be.

The new section in the report on ethics in study design is obviously important and has already played some role in our discussions today. And then the other major change had to do with six and seven being merged.

DR. DUMAS: I donít know whether this should be on our list or not but it emerged just a few minutes ago, and that is the ethics of the purpose of the study, the type of study, not just the design but the purpose of the study.

DR. CHILDRESS: Good. I think that should come into play in relation to the issue of design justification and so forth, at least given the categories we have here, though it could be done in other ways. Letís make sure we get it in.

Okay. If we look at page two at the points for discussion, letís keep one other thing in mind as we work on this, and that is some of the recommendations weíre making actually would call for changes in regulations, others would simply call for additional guidance for IRBs, and then there are still other levels of recommendation as well. So part of what is a matter of our discussion and special discussion with other groups, as came out in Dr. Shoreís report from the conference in early December, has to do with even if we agree that something might be good, advisable to have, where do we want it to play into our process? Do we want it as a matter of regulation, or do we want it simply as a matter of guidance?

I would also note that the staff did a good job in identifying a number of the pages where particular topics are discussed, but there are also others, and so Iíll try to mention some of those along the way if we need those for discussion.

Iíll try to move us through this in a reasonable way. We want to spend as much time discussing any particular topic as that topic merits in our collective and individual judgment. But we also want to think about trying to move the report along.

Letís start with the topic that came up at the very end and then turn to the topic that occupied most of our attention during the last session. The topic that came at the very end is the population this report addresses, and then, of course, the research design topic is the one we spent most of our time on.

The population this report addresses. Thatís already appeared, obviously, in the title which we have discussed several times. We have language addressing this in the text on page 2 and I guess we have a revised page 2 before us, do we?

DR. MESLIN: Let me just say a word. Alex was kind enough to jot his suggestions for revision down on a separate two-page document which has been distributed to you. Three-page document, Iím sorry. It says Chapter 1 and itís stapled and it was just recently handed out.

PROF. CAPRON: I would suggest that we try to be responsive to this question that Jim raises and we can get to that later.

DR. CHILDRESS: Thank you. But on page 2, on pages 12 and following, and then on the pages listed here, we have discussion in this draft of the population. And the question posed is are we satisfied with the description of this population? Keeping in mind that we are talking largely about mental disorders affecting decisionmaking capacity, that does not mean that those disorders affect any particular individualís decisionmaking capacity. Thatís a separate determination. But the presence of the mental disorders would trigger closer examination.

But are we satisfied that we have indicated in the title and in the description in the text the population we want these recommendations to address?

DR. DUMAS: Iím satisfied with it.

DR. CHILDRESS: Any discussion?

DR. BRITO: Well, Trish made a comment about the mention of delirium in here. Iím satisfied with it, but Iím not sure if we should address that right now because Iím not sure if that doesnít confuse it a little bit, on page 13 and 14.

DR. DUMAS: It says somewhere in here that although our primary focus is people with mental disorders, that weíre not ignoring the fact that there are other conditions that can affect decisional capacity. So I think it takes care of your concern.

DR. CHILDRESS: On page 2 in the draft, we note that persons with mental disorders are not, of course, unique in being at risk for loss of decisionmaking capacity, et cetera, et cetera. And we also talk about children and why theyíre different from the group weíre talking about here.

Perhaps we ought to pursue that one with Trish. I donít think she can hear us this morning.

DR. DUMAS: Is her concern that delirium does or does not follow the rubric of mental disorders; it does or doesnít?

DR. BRITO: Her concern is that is shouldnít be separated out like this.

DR. SHAPIRO: Not directly relevant to this, but I thought the materials included in this particular draft which points to the fact that people suffering from other kinds of disorders altogether could have some problems in this area, really responsive to Ericís comments that he made last time, really improve this quite a lot. I feel pretty good about where that is right now.

PROF. CAPRON: I guess whatís important to me is a concise statement of the interaction of the different factors that are going to be present to different extents with any particular patient, but which in a cumulative fashion are likely to cause problems. One is the kinds of illnesses that marginalize people in society, which make them difficult to deal with, which make them frustrating for physicians and others to treat, which often lead to their institutionalization, and where the kinds of research that weíre concerned about are studies on their mental status itself, about their mental condition. And in this sense, they are different from patients whose physical conditions render them less able to make fully informed judgements than a person with no medical stresses in their life because of the very thing thatís under study is their psychiatric condition.

When you have any one of these factors, you have a problem. For many of the patients who are most likely to be vulnerable to well-meaning or otherwise abuses, itís where these things come togetherówhere they are institutionalized, where their condition is progressive, where their families and others are either absent or are not able to deal with them, or society is annoyed by their presence or takes no interest because theyíre no longer productive members of society, et cetera, et cetera.

I donít see that our report finally pulls these different strandsówhether itís schizophrenia, dementias, deliriums, other conditionsótogether and ties them into what I would say is more the sociological as opposed to the medical context that has led to the long lists of problems that provoked this report. And thatís still what doesnít quite come through for me. And youíre right, as to that extent, thereís a little bit of language in these pages that I drafted to try to get at that. But I donít want to get into those.

And it seems to me, even back in the introduction on pages 12 and 13 to the different categories, we are at great pains to say not everybody with schizophrenia is unable to make decisions about their medical care. And we say that point over and over again, I agree with you. But we donít seem to pull together why this group is particularly a vulnerable population.

DR. CHILDRESS: I think if Iíve heard our discussion over time, I think there would be general agreement that we ought to do that and that there are places, for example on 65, where we deal with institutionalization and so forth. But your point about pulling it together and getting everything out and seeing how the different variables may be relevant for decisionmaking, that would be very good to get that up front.

DR. MORENO: Could I just ask, Alex, maybe at some point, and I could focus on pages 22 to 25, which do attempt to do what youíve suggested, but maybe we could see together how we need to improve those, beef up that section.

DR. DUMAS: I think itís very good to be as clear as we can be about what it is that makes this group vulnerable and give us concern about protections. But I caution that we not get into too much detail on specific aspects of this because my feeling about the document as it is, is that our salient points often are embedded in a lot of verbiage. So if you can keep that in mind, that we donít surround the whole thing with circumstances and miss the major points.

DR. MESLIN: Just as a point of procedure. Alex, is it your sense that the strands that youíre referring to are here in the report but they are just not brought together early on?

PROF. CAPRON: Yes. Itís a way of saying what Rhetaugh has said.

DR. MESLIN: Okay. Because I think the strands, if we look at 2, 13, 64, 22 to 25, and 149 to 151, theyíre there but they are strung out. And youíd like to bundle them, to use a computer term.

DR. CHILDRESS: Thatís an important editorial point. Good.

Iím just going to go through and assume that silence means acquiescence. So if anyone has any strong objections as we move along, be sure to express that.

If there is nothing else on population, letís turn to the topic on which we had the very important discussion earlier this afternoon. I think it was actually one of the most fruitful discussions weíve had on this particular draft report. The big question thatís being raised here is where we want to set the presumption in terms of challenge studies, and how those compare with what we want to say about washout studies and/or placebo controlled, and then a few pages are given there where we discuss these matters in the text and I would just add also pages 10, 148 and following, and some others where thereís some discussion. But, of course, the critical ones are on ethics of research design. And also keep in mind Rhetaughís question that the purpose also is important, and any issues about that we can work into this.

DR. DUMAS: I had a concern that we make sure to address the purpose of the study. But I note under this topic of Research Design the concerns that I have are here, they would be treated under this topic. And it has to do with wash-out studies, and what do they call those others? Symptom provoking studies.

DR. CHILDRESS: Alta?

PROF. CHARO: Although Iím certainly open to an alteration of these views, it strikes me that the way in which we generally assess any kind of study, that is looking at the magnitude of the harms that could occur and the likelihood that they will occur, which is what we generally understand as risk, as measured against the need for this study, is a perfectly acceptable way of handling all these different formats, whether itís placebo controlled, standard therapy controlled, washout, or challenge.

I think that in a context of challenge studies itís fair to say that the likelihood that somebody is going to experience a disturbing event is pretty high, because thatís the whole point of the study, but the actual magnitude of the harm that that represents is going to be quite variable depending upon what kind of challenge study youíre doing and the kind of person youíre working with and their familiarity with those symptoms. And that would be part of the kind of discussion youíd expect from a sophisticated review body in the course of figuring out how to assess the risk and then look at whether or not these studies are genuinely needed or if there are less risky alternatives to achieve your goals.

For that reason, my instinct is that rather than create more categories, we would want to subsume this under the more traditional risk-benefit, risk-necessity balancing, and we would want to perhaps in the form of guidanceóand weíll talk later about guidance versus regs versus both tracksóuse these as examples of the kinds of studies that go on and the elements of the discussion that are necessary in assessing the risk of the study.

PROF. CAPRON: I think that I take a stronger view on the washout studies. I recognize the wisdom of what Alta says when she says that things are going to end up being contextual. If youíre washing out someone who has migraine headaches or something and the risk is another migraine headache, itís different than washing out someone who has schizophrenia or some other psychosis and the risk is a full-blown florid episode of psychosis.

What I noticed, however, in Dr. Shoreís answer to these questions as we were asking him, was the problem that I think seems to be unavoidable in this area, which is when you get to do something that seems as adverse to the interests of the person youíre doing it with, you begin to develop rationales. His argument today to us was that he would be more reluctant to engage in, or approve, or think it was all right to do a washout study now that there are drugs which have fewer adverse side effects.

Now, when you think about the logic of that, what that was, as far as I could see, is that it wasnít necessarily without benefit to a person in the old days of those other drugs to go into a washout study because the adverse effects of the drugs were such. But thatís simply the researcher buying into the therapeutic misconception.

People were not being put into those studies because of an individualized assessment that in your case the side effects and so forth from the drugs were such that you would be better off on a lower dose, or no dose, or letís see if you overcome your schizophrenia and you donít need this drug anymore, or whatever the rationale would be for doing it. It was simply that we need patients who are in this episode to see how we intervene to pull them back from it, how quickly we can do that, or what their brains look like, or what their blood levels look like when they are in this, whatever the rationale was. It was the scientific rationale, not for the benefit. But it was darn hard for an experienced investigator to own up to that.

Which then to me, on a research subject side would say, why would anyone in their right mind who is being successfully treated for psychosis agree to go off and become psychotic again. Given everything that anybody has said about what itís like to be in that condition, particularly if youíve been brought out of it and can view your behavior then and what it was like and how distressing it was for you and everybody else, it ó

PROF. BACKLAR: Trish Backlar has her hand up.

PROF. CAPRON: Well, let me pause and let Trish intervene.

PROF. BACKLAR: Okay. When you finish.

PROF. CAPRON: No, no. Trish, I defer to you. Iím so glad that youíre with us.

PROF. BACKLAR: Itís hard to hear it. Itís as though itís a transatlantic call in the 1940s. Are you going on speaking?

PROF. CAPRON: Go ahead, yes. Weíre all hanging on your words.

PROF. BACKLAR: Iím afraid I couldnít hear what was just said.

DR. CHILDRESS: Weíre waiting for you to speak.

PROF. BACKLAR: Itís just that you brought up something that I wasnít sure, I missed the conversation with Dr. Shore and Dr. Rosenstein, and that was I would like to know is, other than the usual methods they use, how they could persuade anyone to be in such a study, in a challenge study? How could one be persuaded? I could not be persuaded. And therefore Iím concerned that the people that you are persuading really do not understand what is going to go on.

PROF. CAPRON: Iím glad you said that because thatís exactly the point, Trish. And, therefore, I would say, given Altaís comment that this isnít totally black and white and there may be some situations in which you would think that the harm would be de minimis or something, I would like us to directly confront this issue.

And if itís appropriate to move, I would say our report should say that it requires an overwhelming burden of persuasion for an IRB to approve any study removing a subject from an effective treatment for their mental disorder in order to study their underlying condition. I would have said they should simply be forbidden. But in light of Altaís comment, perhaps that flat-footed way of putting it is too strong. Because I cannot understand, as Trish said, what you could say to a person that would honestly convey to them what theyíre going to face that would have anyone who has decisional capacity agreeing to go ahead in those circumstances.

DR. CHILDRESS: Go ahead and respond and then I have four others on the list. I have Rhetaugh, Alta, David, and then Eric.

DR. SHORE: I was just going to say, Iím sorry if it was not clear, that people who are doing well on medications would not ordinarily be invited to participate. People who are not doing well under current medication. For instance, during 1978 through 1985 when I was in the intramural program, people came to the inpatient unit at St. Elizabethís for the study of schizophrenia. We never made any attempt to recruit people who were doing well for exactly the reasons you describe. What would they have to gain from going off these medications as opposed to what they would have to risk.

PROF. CAPRON: In other words, you would not object to the standard that I just put forward because you think you were following it. And that may be the case, but we know that research studies have been carried on which havenít followed that.

DR. SHORE: Well, could you give me some examples?

PROF. CAPRON: Yes. Iíve read the research description of the UCLA study and it did not limit itself to people who were failing medication.

DR. SHORE: Well, what it did was to take people who had been able to tolerate three months previously off medications and did well and offered them the opportunity on an open basis to go medication-free for eighteen months. And only if they agreed to that while they were well did the study proceed. Iíve heard a great deal of misinformation about that particular study come from this group and others. But since I, in fact, was the project officer and was present at site visits in 1986 and 1989, I am convinced that I am one of the people who actually knows what took place in that study. It has been, I think, unfairly mischaracterized.

But individuals who consented to be in that study presumably didnít want to continue to take the medication for the rest of their lives after having one schizophrenic episode. Remember, this was not people who had five or six episodes every time they stopped their medication. This was first onset. This was 1985, we had no idea, we believed that a third of the people who developed schizophrenia would get better and never need to take medication again, that another third might have another episode, and that another third would continue to be psychotic. So the people who did well presumably had a 50-50 chance of not needing to take the medication. Therefore, it seemed a valid research question at the time to offer people an opportunity to get off medications that produced a 5 percent per year risk of tardive dyskinesia.

PROF. CAPRON: I donít really want to spend a lot of time. We donít have the protocol in front of us. But when those studies were done and the results were published, the researchers stated that the advantage of their research design over other people who were asking similar questions about the effects of treatment on these patients was that they were dealing with patients who had been brought to a relapse, a full relapse. So they intended some of the patients in that study on the predictive basis you were just describing, I donít remember that it was a third, were people who would fully relapse and who could, therefore, be studied in that condition.

DR. CHILDRESS: Just a very brief response so we can move on to the other questioners.

DR. SHORE: If you read that paper carefully, and, believe me, I have, most of the people who relapsed in that study were on medications. And not all of the people who were taken off medications showed a relapse. And in point of fact, what they did was simply look at the people who deteriorated very rapidly and went to the point of relapse during the two week interval between the follow up visits. They did not, despite allegations to the contrary, they did not allow people to show clinically significant deterioration without recommending that they go back on medications. Thatís another fallacy of the study thatís been repeated so many times that people believe it. But if you read that study carefully, you will see that most of the people who went to relapse were, in fact, continued on medication. And that was not the design of the study to produce relapse.

PROF. BACKLAR: May I say something? I apologize if this has been discussed, but it seems to me, David ShoreóDavid, was that you speaking just now?

DR. SHORE: Iím here.

PROF. BACKLAR: Was that you speaking just before?

DR. SHORE: Yes.

PROF. BACKLAR: Iím a little concerned about something that I think I heard you say, which was that you only invited people in to a challenge or a washout study who were not doing well on their medication, and that if they were doing well, you didnít approach them. And if they were not doing well, it seems to me you would come to confusion there because it would appear that maybe youíre developing a kind of therapeutic misconception as though they were going to be helped being in a study. Am I missing that?

DR. CHILDRESS: Trish, in order to move it forward, I think this is helpful, but weíre going to have to move away from the UCLA study and really address the two kinds of questions that we have before us. We have Altaís proposal to treat this the way we do any risk-benefit analysis, just make our judgments within that context. And then Alexís proposal that, no, we come down with a much stronger presumption in this area.

I have Rhetaugh, then Alta, and then David, and then Eric.

DR. DUMAS: I would like to speak for the possibility of those patients who can give consent to have the opportunity to participate in those studies if they choose to, even though I myself might not choose to do that. And I think that we need to be very clear about the kind of protections we would want to propose to take care of the concerns that people have rather than eliminating the option for the person to participate in the study.

PROF. CHARO: I think the question of why anybody would volunteer for this is a very good one. It goes to the heart though of all people who go into research experiments where there is little or no prospect of personal benefit, medically speaking.

I speak now out of the experience of having been a research subject many, many times. A lot of times people go in because of ancillary benefits. Some are financial, some are the opportunity to be seen and interviewed by physicians other than the ones they usually deal with, sometimes itís because they simply feel theyíre going to get more frequent attention, and some do it because no matter how many times itís explained that there is little or no prospect of therapeutic benefit, thereís a secret deeply held belief that their really is a therapeutic benefit out there for them somehow.

Itís this last concern that I think is rife through the entire area. It is particularly rife in this area, as weíve seen. And I am thoroughly and genuinely concerned by it. I still feel that itís possible that a well operating IRB, and thatís an important condition, can take this into account when they look very hard at a study design, look very hard at the particular population that is being recruited and ask not only what is the magnitude of the harm and the likelihood of its occurrence, but look at harm not only in absolute terms but as the difference between where somebody is and where theyíll be if it comes to pass, which really does make the picture look different when you looking at somebody who is doing well who might now crash versus somebody who is doing poorly and might crash.

This may not be a happy thing though that people who are doing poorly should be more easily exposed to an even more miserable experience. But this can be part of I think a good discussion. In some ways a realistic question here is whether we think that IRBs, with examples and explanations, can handle this, or if thereís so much skepticism about the ability of IRBs across the country in every possible institutional setting to manage this that one wants to draw brighter line rules.

That may be the way to go at this is to incorporate how much you trust IRBs to be able to handle this. Because I agree that, in large part, these are going to be the most difficult kinds of studies to justify for these populations, even if analytically I think they do still fall along a spectrum.

DR. COX: Iím in favor of a brighter line for the reason that I said earlier. I really do care about the therapeutic misconception, but I care about the benefit to research misconception. Itís very easy for someone to say that this is outstanding research when itís garbage, and to have vehicles to really adjudicate that issue is very difficult under the best of circumstances. So I think that if we donít really make a bright line on this, itís just going to fall by the wayside like so many things do. The therapeutic misconception is bad enough, but the research misconception is even worse for me personally.

Thatís not to say, though, I would feel extremely uncomfortable about saying that we, however well-meaning we are around this table, could decide for other people whether they should do something or not. Iím extremely uncomfortable with that. So Iím with Rhetaugh on that. But for the two reasons, both the research and the therapeutic misconception, Iíd like a bright line on this one.

DR. CHILDRESS: Eric, and then Iíll get Harold in on this issue.

DR. CASSELL: There are patients who want to be off their medication because they really believe that they donít need medication and, yet, itís not clear whether they do or they donít. I think that they should be permitted to come off medication if they can give consent, but with the extra protections that we have given elsewhereóinformed consent, plus a representative, I want to discuss the word "legal" another time, plus a representative, plus the physician from outside the unitóso that theyíre protected to the degree possible. I think if thatís what they want to do and the research has been looked at, they ought to be able to do that.

DR. CHILDRESS: Harold, and then Larry.

DR. SHAPIRO: I had a series of comments on this and let me just try to keep it very short. I think we should specify once, and perhaps not have to repeat it over and over again, that we are going to have a very strong section on study design. Everybody agrees. I think Iíve not heard any disagreement about it. And thatís going to have to inform this perhaps in a more thorough way than currently exists in the report.

With respect to the issue of drawing a bright line or not, I guess, as I listen to the comments, I think people have different idea what that bright line is. So, for example, I would be against prohibiting this or outlawing it, as someone suggested before, and I didnít interpret Alexís statement as suggesting that either. And so itís really a question of whether we think this deserves some special notice because of the concerns that swirl around these studies. And I sense that we all think it deserves some special focus here in some way and that itís just a question of fashioning language which is not so restrictive as to put people in a straightjacket but would highlight it in some way, that would draw the attention of the IRBs and others to their responsibilities.

Iím somewhat unsure, although I find, Alta, when you made your comment, I found it really quite persuasive as it went along. I kept saying, yes, that sounds very sensible and so on. But then I took a step back and said, well, but this is what they should be doing in every study there is, thereís no exception from that. And so that I think if we could find some language that would highlight this in some way that is not overly restrictive that would be very helpful. I donít have any language proposed, I havenít set down.

Alex, I couldnít quite decide whether I approved of the language or his enthusiasm was getting in the way, because somehow I felt he was going too far but it may have been his enthusiasm as opposed to the language. I didnít quite get all the language, so I would have to see it. But thatís where I feel we ought to be.

DR. CHILDRESS: Larry, then Eric Meslin.

DR. MIIKE: I think Iím awake now so I guess I can say something.

DR. SHAPIRO: Welcome, then. Weíll ask you again when youíre sleeping later.

DR. MIIKE: My comments are going to be similar to Haroldís. Iím interested in what weíre talking about a bright line. If bright line is absolute prohibition, then I couldnít agree with that. I guess it boils down to what some of the presenters wereóI think there was one slide up there where the intent was to cause a harmful effect versus a high probability of a harmful effect in a study design. And so if the intent is to cause a harmful effect, then we obviously need more safeguards.

But I think the spectrum that weíve been talking about should be able to handle that. I donít think we should be getting into individual instances or individual examples to carve those kinds of things out. We need an approach that handles everything.

DR. CHILDRESS: I would just say in addition to that, it seems to me that there have been different perceptions of harm, not only in our discussion today with our two previous presenters but in some earlier sessions as well. I take it that many on the Commission are willing to refer to, to use Joel Feinbergís language, to setback the interest that occurs when one becomes very distressed and the like as a harm, whereas some other discussions have tried to look at something other than that, seeing that as not quite counting as a harm. But I hear much of the discussion on the Commission at least as including that as a harm.

Eric?

DR. MESLIN: As a suggestion for moving forward with language, I just want to draw the Commissionersí attention to page 30 and 31, where this issue is raised and offer a proposal. The staff report mentions line 6, for example, on page 31, deciding which design will best answer the research question, what procedures will be used, et cetera, have both scientific and ethical justifications. What Iíve heard from Harold is that thatís the right direction and itís the degree of specificity or the burden of expectation that an IRB would have of an investigator who provided such a design in a protocol, that that would be appropriate.

If the phrase, the two options weíve given in the memo that challenge studies are, in general, ethically problematic but under exceptional circumstances permitted. And we phrased it in an extreme sense. It sounds like Commissioners might like to see that IRBs should be especially careful in scrutinizing those proposals in which the designs raise profound ethical questions, and we should not be shy in saying, for all of the reasons that have been indicated, that this set of designs raises particular questions. Altaís suggestion that the scrutiny of IRBs in the risk role I think is entirely consistent with that proposal. But if you are asking us, I would propose that we flesh out lines 6 to 8 along this direction.

DR. CHILDRESS: I guess the question before we do that is whether there is general agreement that we want to say that challenge studies are, in general, ethically problematic but under exceptional circumstances permitted. If thatís the direction. Now, here we may get the tension between Altaís formulation and Alex.

Itís sort of where you set the presumption here that seems to me to be the critical matter, and that the bright line really is once this appears, then look at it very, very carefully, and you have to have very strong, maybe overwhelming, but you have got to have a very strong justification for going forward with the research of that sort.

DR. COX: Jim, Larry and Harold were right, when I was using the word bright line, most of the time people mean that thatís like a prohibition. For myself, thatís not what I meant. What I meant is it should be able to go ahead, as Rhetaugh said, but I believe that itís special, not just because itís a challenge test, but because of something that Alta said earlier that I thought articulated it beautifully; that is, that it was either an intent or a high likelihood of a harm. Now, thatís an unusual way to do experiments. Thatís what makes it unusual for me, not that itís evil, or not that itís always going to do a harm, but that thatís the reason to highlight it. Thatís what makes it different.

So, without sort of turning that whole line of scientific inquiry into an evil, which I wouldnít be keen on doing, it gives an ethical reason why to distinguish it from other things, and not to prohibit it, but to say that people better look very carefully at it. And then it strikes me that that is hitting what everybody is saying. Maybe not, Howard. Maybe itís too wishy, too wimpy.

DR. CHILDRESS: Okay. I have Steve, then Alex.

MR. HOLTZMAN: I can imagine a challenge experiment in which Iím provoking a physiological adverse reaction in a normal subject, one in which Iím provoking a psychological adverse reaction in a normal subject, and one in which Iím provoking a psychological adverse reaction in a person with limited mental capacity. When weíre talking in this discussion about challenge, are we talking about all of those cases, just the last two, or just the last one?

DR. CHILDRESS: Alex, then Rhetaugh.

PROF. CAPRON: The focus of what I was saying about triggering special concern was actually the wash-out study. As to these different challenge studies, I think Dr. Rosenstein was provocative. Eric answered why he thought it wasnít a sufficient response, but he kept saying there are circumstances where for diagnostic reasons, for example, one provokes a physical symptom.

MR. HOLTZMAN: No, see, I was very moved by Altaís point about itís in the nature of this to produce ó

PROF. CAPRON: Well you put someone through a cardiac stress test that can do them harm but youíre doing it in the context of diagnosing and treating their condition. What I just see as a thread running through this is a therapeutic misconception. And I ask myself, it isnít just subjects who are befuddled and desperate or whatever, itís time after time that the consent forms themselves slide into suggesting ways in which this will be of benefit to you. Because I think it is just so hard for people to face up to the fact that theyíre putting someone at direct risk for scientific purposes. And if this were a person who was under no obligation, psychological or medical, to participate in this study and so forth and you said you had the astronaut willing to take off into space at the risk of never coming back or something, you might at some point say, sure, itís okay for two people to reach that agreement. But we know with this population or many members of this population there is a history of abuse of that misconception.

And I just want IRBs, with language, Eric, weíre looking at the transcript to get this, language that is stronger and more direct than the language you suggested to be told that the need for scrutiny, the need for monitors, the need for second opinions and outside doctors making sure the personólook, if you want to go off, we can get you off your drug without you going into this research project. Just so that thatís really clear. If a person says, no, I have schizophrenia, a lot of people have schizophrenia, I really want to be the person who helps to contribute to understanding this disease, and I know Iím in a lot of risk, and I know Iím going to get nothing out of this, but Iím just the most altruistic person in the world, I want to do it. Theyíve gone through everything and the research is really going to show something, David, I wouldnít make it absolute, Iím with Alta, I think it shouldnít be absolute, but it should be harder.

And frankly, Alta, to answer your question, Iím a lot more comfortable with a committee that has David Shore on it who has looked at this subject inside and out than the IRB at Podunk Hospital, which happens to have a mental unit, when somebody comes in with some idea theyíre going to do some research and (a) David says itís not going to be scientifically as good as what goes on at NIMH; and (b) that IRB, unless this has already been waived to them because this is a special concern, theyíre not going to know itís a special concern and they may approve it without the scrutiny it deserves.

So I want us to say this is something which in the regulations you are required to do special review for this ó Iím sorry if my enthusiasm diminishes the effectiveness or persuasiveness of my point here.

DR. CHILDRESS: I think weíre pretty close and it may just require now that we actually get wording worked out, staff to do it.

Let me take three quick comments and then see if we can move on to another topic. I have Rhetaugh, Alta, and ó

DR. DUMAS: Iíll pass.

DR. CHILDRESS: You pass. Okay. I have Alta, then Eric.

PROF. CHARO: I think Eric was actually ahead of me. So, go ahead.

DR. CASSELL: To be very short about it, I want to just underline what Alex said, but in my usual quiet, calm way. And I want to also point out that in the discussion in the report the history has to be mentioned so that people understand this isnít just an arbitrary, oh, they didnít like that kind of, that this has a history and that is part of the reason for the strictness with which we have dealt with this topic in general. Understanding that, then IRBs will be put on notice, and they should be.

MS. CHARO: I have no problem with the idea of a guidance to IRBs that says that as a whole washout placebo and challenge studies with this particular population tend to representótend to representóthe most extreme examples of every ethical problem that has been associated with these areas of research to begin with. And that on that basis that every tool in the tool kit for special protection should be considered and that the scientific merit should be given the greatest possible scrutiny in order to make sure that we have a reason to be doing this at all.

I do still have a problem with the idea of trying to carve out a subset of these things and call them ethically problematic in a way that is substantively different from all the others, partly because of what I said before about them being on the spectrum, but also because as soon as we do that I think then weíre going to have to negotiate very closely on is it only wash-outs, is it wash-outs and challenge, wash-out and challenge of placebo, is it all of them, some of them.

The more that you try to get specific about carving things out and saying you must do these things for this particular category, the more important it is that youíve carefully defined the category. The more that youíre simply pointing IRBs in the right direction, the more flexibility there is in your description of those circumstances that should be noted for them.

And so for that pragmatic reason, I would prefer something that avoids classification but simply identifies these and says, "Weíve seen every problem imaginable in context with these and they deserve your extra attention above and beyond the extra attention in general."

DR. SHAPIRO: I think weíre getting close enough here, Jimó Iím sorry, I didnít mean to interrupt.

PROF. CHARO: That was it.

DR. SHAPIRO: I think weíre close enough to move on. We do need to redraft the language along the lines that reflect some of these ideas here. As I look at the memo itself, as opposed to language in the report, I think the report is not strong enough, this language may be too strong. But I think weíre close enough to produce a reasonable draft that reflects these concerns.

DR. CHILDRESS: Eric was suggesting that maybe some people who are particularly interested in thisóAlta, Alex, Rhetaugh, or anyone else whoís interestedómight actually want to try their hands, even tonight, and see about getting something drafted, a kind of direction for the staff that could then be amplified. Is that agreeable? If thereís nothing else on research design, letís turn to the other topics. I think it was important that we spend a fair amount of time on that one since itís the one that has bothered us for a while and we had some good discussion on today.

Capacity assessment instruments. We require investigators in this, IRBs ó page 2 of the memo. Investigators are required to justify their chosen manner of capacity assessment in the protocol and that will then be reviewed by the IRB. Does that go far enough? This is discussed in the text at 170, at 71 and following, as well as 72.

DR. CASSELL: It seems to me a reasonable thing to do, you know how I feel, because I think thereís so often impairment. But on another side, weíre trying to get further research on the instruments to measure impairment and this helps do that and it ought to keep that pot boiling. It doesnít rule out instruments, but it keeps it going.

DR. CHILDRESS: Eric?

DR. MESLIN: Just very quickly. In the second flow chart that was handed out to you just moments ago, we can go through it another time, but this may be just a point to flag for you. If you see this, I donít know whether we need to put it on the overhead if everyone has one in their hand, but the audience might not. All I want to point out is an issue that Jonathan raised to all of you in an E-mail, and that is the capacity assessment activity could occur in two places. The first place that it can occur is in determining whether or not individuals are capable with respect to informed consent to join the trial in the first place. But the second place is that individuals who are capable may, during the course of a trial or the course of a study, become relatively or completely incapable, in which case the question arises, "Should some other type of ongoing capacity assessment activity occur?"

The staff and Jonathan were sort of struggling with this. I confess that we werenít able to solve the problem. You see in that very complicated flow chart the middle two boxes, approve the investigatorís justification for assessing capacity, thatís the IRBís job. They canít approve an instrument, as we know there arenít instruments that have been validated. But I just raise this as you discuss out loud that there are possibly two places at which assessment of capacity will occur.

Jonathan, do you want to add anything?

DR. CHILDRESS: Are we satisfied the way the report goes on this with the amplification in the flowchart?

DR. CASSELL: Well, weíre sort of left with the problem of fluctuating impairment, arenít we.

PROF. CAPRON: I have one question, and itís not on the pages identified in the memo, but on the pages beginning at page 79 in the draft. That is the substantive issues. It seems to me that the question that we donít fully grapple with is whether, again, we expect IRBs or somebody to evaluate the appropriateness of the method that is going to be used. And if so, what questions we would have them use, particularly, again, an IRB that may not spend a lot of time in this field, in making their evaluation.

And perhaps you wonít be surprised to know that Iím somewhat of the view that some good questions were raised by Professor Elyn Saks in her presentation, the gist of which, putting aside a lot of questions that arose about some of her particular arguments, is that there are certain normative expectations that are to a certain extent implicit in and to a certain extent even buried in instruments which an IRB may regard as "scientifically validated" and not be aware that in the process they are, in effect, answering what I would call a fulcrum question in our flow charts and in our whole conception, which is, the person who is found to have impaired capacity and not be able to make the decisions for him or herself is one who in certain circumstances is going to have the decisions made on their behalf by somebody else.

And the gist of that is that if youíre applying an instrument that equates lack of capacity with particular responses on the instrument, you are in effect embedding in those responses the sense that this is a person who deserves to have their decisions taken out of their own hands. In other words, itís not simply a protective description of the person, itís a presumptive or taking over of the person by an outside, beneficent perhaps, but outside process.

And if I were on an IRB that hadnít spent any time on this, I would want to be able to read this report and see that issue flagged more clearly. That the reason that you care about this is that the instrument thatís going to be used is going to have real effects on what people can decide for themselves and what others can decide for them. And some of the questions that are asked may presuppose, most obviously, the question of do you know you have this psychiatric illness, may presuppose correct answers that this is normative for the correct answer when the person may be equally as capable as someone else in making decisions but just rejects that rubric as being something thatís being imposed on them from the outside.

And itís important that IRBs say weíre still comfortable having that done, or we donít want that part of the instrument used, or something. I would like to see us be a little clearer why this is an important issue.

DR. CHILDRESS: Eric?

DR. MESLIN: Can I just ask Alex whether the paragraphs beginning on line 13, page 69, preceding ó

PROF. BACKLAR: Can you speak up louder?

DR. MESLIN: Sorry, Trish. Iím just asking Alex and the others to turn their attention to page 69, in fact the lines before then which try to flesh out some of those reasons. Are you thinking that we need to identify another section that sort of highlights for IRBs here are the things that you really need to be thinking about, given that we canít tell them to assess a particular instrument?

PROF. CAPRON: Yes, Eric, thatís the question. Are we in a situation where itís just going to be catch as catch can, that the real thing that IRBs are going to say to people is simply use some recognized instrument and theyíre not going to care whether the instrument is full of presuppositions which theyíre never going to be told about and theyíre in no position to do anything about therefore. And the answer is no.

The stuff on page 69-70, as I read it, has to do with the notion of either progressive or intermittent impairments of capacity. Thatís not what Iím talking about. What Iím talking about is the fact that the questions you ask, which we rather blandly describe as performanceó

DR. CHILDRESS: Performance capacity.

PROF. CAPRON: Page 73, line 3, any assessment tool measures capacity indirectly through manifest performance and our performance does not always reflect our capacity or potential. Thatís one problem, which is you can take a test and do poorly on it when you really know something. Iím talking about the judgment that whether or not you answer a question a certain way indicates that you ought to be judged incapable of making decisions for yourself, not because it doesnít accurately reflect, it perfectly accurately reflects the answer you want to give and the answer you believe to be correct. Itís not that youíre wavering or that youíre under pressure and youíre not taking the test well, itís just that thatís an answer.

If I ask you, "In what year did Columbus discover America," I gather that thereís an agreed upon answer to that and if you say something else, youíre wrong. If I ask you whether or not you have paranoid schizophrenia and you say, no, I donít, but if I ask you, "Do you do the following things," and you were to say, "Yes, I do," whatís the difference? You reject the label paranoid schizophrenia. Now should that mean, as it does in the Appelbaum-MacArthur instrument, does that mean that you are judged one count against you on your capacity.

Now if youíre on an IRB and you donít know that thatís one of the ways that thatís calculated, you wonít know that autonomy is being undermined by that instrument.

DR. MORENO: Can I just make a couple of comments?

DR. CHILDRESS: Jonathan, then Steve, then Harold.

DR. MORENO: First of all, you know, Alex, that Columbus didnít discover America, but never mind. I have also been concerned about this question. Itís something like the general problem that IRB members have, that they donít necessarily have expertise in the methodology thatís being used in the study or thatís being proposed as use in the study. And yet, again, itís different because capacity, as we agree, is a different and threshold issue for participation, particularly for this population.

I donít know how to make much headway with that issue except to note that there are other protections here that help perhaps with your concern; namely, the additional membership which should include at least one individual who is professionally competent to evaluate the instrument or the process for assessing capacity. And another, which I think is not unimportant, is that this requires investigators to go on record and, perhaps by going on record, to be more aware about what theyíre doing and how theyíre doing it. And for a third point, should as well, as somebody mentioned before, stimulate further research in the development of instruments like Appelbaum-MacArthur and others.

PROF. CAPRON: Right. But do you think that the first two points you made Iíve missed in this report?

DR. MORENO: I hope not.

PROF. CAPRON: Can you point me to them?

DR. MORENO: To those points?

PROF. CAPRON: Yes.

DR. MORENO: Well, Columbus is not one of the first two. You mean the additional membership in the IRB, which ó

PROF. CAPRON: And the self-scrutiny of the investigator by having ó

DR. MORENO: Is not mentioned, no. Good example ó

PROF. CAPRON: Those would be steps in the right direction.

DR. MORENO: Good. Thank you.

PROF. CAPRON: Now let me just finish the loop of my thinking. One thing could be to say we donít realistically expect IRBs to do anything about this. In which case, rather than simply say we hope there will be more research in this area and we ought to stimulate the research, we might say as a recommendation, not for regulation but for NIH responsibility, that NIH should have a task force that looks at this issue and puts forth for IRBs an evaluation of different instruments so someone doesnít come along and say, well, Iím using the Capron Scale that he published in the Hastings Center Report or something about how to do assessments of capacity when the people in the field say thatís garbage. The IRB doesnít know it.

DR. MORENO: We do have a recommendation to the NIH to sponsor more research on the general question of consent. But we can more specify it along those lines.

PROF. CAPRON: Right. If we concluded that IRBs are not going to do the function well, is the function going to be not done by anyone, or is it going to be done by some other body that might have enough expertise to provide a guidebook to IRBs about this or a three-page pamphlet, in which they would be told what the issues are.

DR. CHILDRESS: Okay. I have Steve, Harold, Larry, and Eric. And then perhaps we should move on to the roles of other decisionmakers.

DR. SHAPIRO: I think this issue is an important one because of the impact it has to take away decisionmaking capacity from someone. Therefore, it is, as Jonathan or someone said here a moment ago, a threshold issue. My own recollection of the Saks paper is that she did raise a number of very interesting points there which are relevant and not reflected in here.

I would support going back and thinking about that carefully and seeing what we might want to include here as a way of making people sensitive to this issue so they might at least have a chance to think about it. I would also support some guidance to NIH on this of the type that Alex, some of it is in the back of this report and you may want to change that some. But I think some move in both those directions I would support.

DR. CHILDRESS: Eric has reminded me that Elyn Saks is still revising the paper and weíll be getting another draft.

Larry?

DR. MIIKE: I just have two contradictory statements to make. My first is, and itís a constant spiel that I make, is that weíre getting to discussions where itís the cookbook approach. We want to give so much detail when I think weíre a policy guiding Commission. And so I get frustrated when we get into these very detailed discussions.

On the other hand, I hear Eric saying, well, that point is on page 69 on line 7. And so if there are important points, then theyíre buried somewhere all around in the report. So Iím listening to this and I guess what Iíd like to see the staff do is that those points that the Commission raises as important be given more visibility, and maybe not in the sense of redrafting the whole report, but those are the kinds of points that have got to be pulled and summarized in the executive summary.

So those are my two contradictory statements.

DR. CHILDRESS: Eric, and this will be the final one.

DR. CASSELL: Well, all this raises once again, though I donít expect us to settle it, it raises two questions; one, of the consent monitor in certain circumstances, and the other one is the training of investigators on obtaining consent. It always comes around, the same set of issues, and somehow or other we have to, I think in this report or separately, address the fact that investigators must be specifically trained and/or that there will be monitors. That ought to motivate them.

DR. CHILDRESS: That leads us then, if thereís no objection to the next question, but keeping in mind the ó

PROF. CAPRON: I do have an objection. Eric, the problem with that is this is not a consent issue. This is whether or not we deal with consent or we deal with permission from a legal representative. If you go down the chart that was passed out today, and youíre over here on, even on the beneficial research ó

DR. CASSELL: I understand that.

PROF. CAPRON: The subject doesnít have capacity. The subjectís consent isnít even in the picture.

DR. CASSELL: I understand that. But by knowing that the monitor and the consent part are more rigorously dealt with, it pushes the importance of finding out whether that person have the capacity to consent, thatís why.

DR. CHILDRESS: Okay. So staff will follow the discussion and change when they contradictory or amplify the draft. The next set of questions will focus on other decisionmakers. In the draft or proposed recommendations we have legally authorized representatives, independent physician advisors, and consent monitors. So the question being raised here, and there are several other pages for the legally authorized representatives, 74, 77, 114, 133, 195 ó

PROF. BACKLAR: Can you speak louder.

DR. CHILDRESS: Sorry, Trish. I was just mentioning additional pages, I wonít run through them for you, where some of these are discussed. We can talk about those pages later. But the big question here is whether the roles of these three decisionmakers are clearly described in the current draft, and whether commissioners agree with the proposals for each of these, their use and their function.

Here, again, you may want to look at the flowchart or at the recommendations. Here you might even find the simplified, the earlier flow chart useful for identifying pretty clearly.

Eric?

DR. CASSELL: I raise the question I raised in the E-mail about what about states in which the family is not a legal representative, does that exclude the family from this process? Why does it have to be a legal representative rather than a family, first degree relative, or legal representative, and/or, so that we donít exclude the family.

DR. MORENO: Iím not a lawyer, but my understanding is that this is not a prescriptive term, Eric, but a descriptive term. That is that as a matter of practice anybody who has the authority to do this in a jurisdiction is going to be legally authorized. Now thatís not necessarily going to be recognized by statute, it will be part of the common law, through the case law of that State. I donít think we have any way to avoid that.

DR. CASSELL: Well, in New York State until just recently the mother and father, for example, were not legally surrogates.

PROF. CAPRON: No, Eric. The situation varies from State to State. For a long time there was simply no statutory law and actually no decisional law that recognized the common practice, for example, of having spouses consent for each other when one of them was in surgery and you have to get someoneís consent, or one of them is in an accident and you have to get someoneís consent. Minor children, yes, it was quite explicit the parents were the natural guardians of the children. But that practice went on.

In twenty-some States I believe now, maybe slightly more than that, there are these family decision acts which allow a specified rank ordering of people to step in and decide in the absence of direct directions. In some states, like New York, people without explicit authorization from a court, as I understand it, are not going to be allowed to make certain categories of decisions, however.

DR. CASSELL: They couldnít make a DNR decision.

PROF. CAPRON: They could not. And in many States there are particular restrictions on people making judgments about mental treatments or enrollment in research, and the generally drafted surrogate decisonmaking statutes, like durable powers of attorney for health care and so forth, explicitly exclude in most States, I believe, treatment for mental illness, or shock therapy, or institutionalization. Those are not things which you can consent to without going to court and being appointed a committee or guardian of the other person.

So itís going to vary all over the place. But Jonathan is right that there will be people who are regarded as the legal representative and can sign off on a lot of things who havenít gone to court to be approved just because the State has allowed that as a practice and no one has ever challenged it. Itís a kettle of fish though.

PROF. BACKLAR: On the other hand, it would be quite dangerous. I would be very concerned if a public guardian could make decisions like this.

PROF. CAPRON: Public guardian? This is for a person who lacks a family member, right?

DR. MORENO: We try to manage this problem in the recommendations by including some suggestion to state legislatures, at our peril, that they devise statutes that include specifically family members as representatives of this kind. Obviously, the Federal system being what it is, we canít do this for the states.

PROF. CAPRON: On page 175, what about Trishís concern about the public guardian who are legally authorized to make treatment decisions. At the bottom of our chart, should they be the legal representative who can consent, as it were, give permission if thereís no apparent dissent from the mental patient?

DR. MORENO: Good question. Itís not one we considered.

PROF. CAPRON: Among the most vulnerable people, again, are those who are not befriended, as it were, those who have to rely on the so-called public guardian.

DR. CHILDRESS: Do you have a recommendation on this?

PROF. CAPRON: I would say that the public guardian should not be in a position to act as the legal representative to enroll people in the research.

PROF. BACKLAR: It varies, you see, from State to State.

DR. SHAPIRO: I just ask a question of information. There are, unfortunately, increasing number of people who are legally giving up the guardianship of their children really to make them eligible to enter state institutions and to come under State guardianship. Is that the group weíre talking about here? If not, how does that group fit into what weíre discussing?

MS. CHARO: Harold, thatís not actually the group weíre talking about, but it does give one an idea for guidance because the same question is going to be coming up with children. What are the residuals of decisionmakers when parents are not around? What are the rules that govern with regard to things like public guardians for children? And it may be that there are a set of workable rules that we could parallel, or it may be that weíll discover there are no rules there either, but either way actually it might be valuable for this discussion to see whatís happening in that analogous area.

DR. SHAPIRO: The population I was thinking of, although I didnít describe it very well, were children and/or people, primarily teenagers, who have very severe psychiatric symptoms which require extensive treatment of very expensive kind. And just for good or ill, in a lot of those cases parents are giving over guardianship to the State, who then takes over their care. Thatís, unfortunately, common. I just donít know how that fits in here. I guess youíre saying we havenít worked that out yet, is that right, Jonathan?

DR. MORENO: Youíre right about that.

DR. SHAPIRO: Okay. Then thatís something weíve got to think about.

DR. DUMAS: Iím going on to another question that I had. In this group where there are not potential benefits, down on the right-hand column, indicating informed consent and legal representative and physician. Can somebody tell me why the health care provider is limited to the physician when in these settings there are other therapists?

DR. CHILDRESS: On the first draft, we have in the text where we had the flow chart, actually it says health care professional monitor. The question was why we had only physician on this draft you cannot see because it was just handed out today when on the previous flow chart we actually had health care professional monitor.

DR. CASSELL: Iíll tell you why. Itís a question of power politics in the research unit. If there is a physician available, that physician will have more power vis a vis the people running the research than the psychiatric social worker will. If there isnít a physician, then it should be another caregiver. But thatís the only reason. It was really to give that patient more crunch on his or her side.

DR. DUMAS: Well, I donít think we ought to continue to reinforce it.

DR. SHAPIRO: I donít think you can change it in this.

DR. DUMAS: And because there are some units now the directors of the units may be a psychologist or a social worker or even a nurse.

DR. CHILDRESS: Trish, do you want to get in?

PROF. BACKLAR: Well, itís very hard for me to tell exactly what youíre talking about. But if you are talking about what it sounds like, I also am concerned, and Eric, I think you and I have talked about this. Many people have psychiatric disorders who hardly know their physician, their prescriber. Theyíre much more likely to know their caseworker.

DR. DUMAS: Thatís right. Caseworker.

DR. CHILDRESS: So, if Eric Cassell doesnít object, weíll go with health care professional monitor?

DR. DUMAS: Yes. Even if he objects.

DR. CASSELL: I do object. I do, because what will happen, by doing it that way, remember that the team goes to pick this person, it isnít the patient that picks this person, the research team picks this person. They will pick the weakest one they can get.

PROF. CAPRON: An IRB could designate the person.

DR. CASSELL: Well, then make it physician or, if not available, other health care worker. Or primary health care worker.

DR. DUMAS: Primary health care worker Iíll agree to.

DR. CASSELL: Physician or primary health care worker.

DR. DUMAS: No, not physician.

PROF. BACKLAR: You know, Eric, I think youíre absolutely right. I think youíre right not only in the sense these people have more power, but also because I think all these people should have at least some acquaintance with somebody who is prescribing their medication. So Iím not going to argue with you about having it there because I think itís good. I do think itís going to be a problem.

DR. DUMAS: We said therapist is fine with me, but I donít think it should be limited to physician. Theyíre not the only therapist.

DR. CASSELL: It isnít limited to a physician.

DR. DUMAS: The responsible therapist would seem to me to be the case.

DR. CHILDRESS: Should we say instead of this the responsible health care provider, whoever it is.

DR. CASSELL: Well, it may not be a health care provider. They may have no outside health care provider.

DR. CHILDRESS: But weíre requiring that on this.

DR. CASSELL: No, weíre requiring a physician. The physician did not have to be a health care provider.

DR. CHILDRESS: Larry is trying to get in, then Harold, then Alta.

DR. MIIKE: Just a little aside thing just getting back to the term "legal representative." It is confusing when in the recommendation there is a recommendation to State legislatures to legislate legal representation, including family, et cetera. So weíre using legal representation both in a general term and in a legal term. And because legal representationóby the way, Iím one of those legal guardians in a state that deals with children and adults that you talk about. And if there are questions about who you exactly want to be able to make these decisions in the mental health area, maybe we should just find another word, "authorized representative" or something, just so that thereís no confusion about the term "legal."

DR. CHILDRESS: Could several of you, particularly those with legal background and experience, such as Larry, and concerns about power, Eric, get together over some of these categories and make sure we get the ones right?

DR. DUMAS: The power struggle is here, thatís where it is.

PROF. CHARO: Iíd like to talk to this because I fear that if we continue debating this weíre debating something that gets down, as Larry has said before, to a level of specificity that almost obscures our goal. If what weíre doing is creating a tool box for IRBs and we say to the IRB that when youíve got certain kinds of red flags we want you to use these tools, itís probably sufficient to say to the IRB we want you to have an independent consent monitor.

And in the discussion, in the more elaborated form, not the short form, we would be acknowledging probably the way this is going to happen is that the research team is going to propose somebody, their name is going to be mentioned to the IRB, members will have a chance to see if that name raises any red flags, but otherwise theyíre going to pass on it. But point out to the IRBs that the purpose of this consent monitor is to give, as you put it, crunch to the patient, and that they should keep in mind the effect of professional hierarchies in the effectiveness of this monitor but also the actual personal knowledge of the patientís situation, preferences, and patterns of behavior in the past.

And, again, it will be on an individualized basis that this whole thing gets reviewed. But the point is that youíre signaling to the IRBs that there are all these things that go into the consideration, please take note of it. I doubt that we can come up with a word or a rule here that governs every situation equally well, nor do I think weíre trying to draft regulatory language that attempts to do that.

DR. COX: You just said it. Write it down.

DR. CHILDRESS: Thatís right. Youíve already taken the discussion forward.

PROF. CHARO: But weíve got all these transcribers here for $10,000 a day.

DR. CHILDRESS: Harold?

DR. SHAPIRO: I had a comment similar to the one that Alta, a suggestion that was similar to the one Alta made. If I understood Ericís suggestion, it seems it was that you wanted physicians to be in the list, that is you said "physician, or something of that nature." So it wasnítóand you just donít like physicians on the list?

DR. DUMAS: No, he said only if there is not a physician, then somebody else.

DR. CASSELL: Just that way, physician, or, or, or. Weíre trying to solve your whole groupís power problem thatís as passé as anything could be.

DR. DUMAS: No. My problem is already solved, Eric.

DR. CASSELL: Not yours. Youíre powerful.

DR. DUMAS: I agree with Alta. I donít think we should be so specific. And she said it really beautifully. And I would be glad to go along with that.

DR. CASSELL: Iím happy with her language.

DR. DUMAS: So that takes care of it.

DR. CHILDRESS: We have consensus. Iíll let Harold finish, and then Steve.

DR. SHAPIRO: Iím through.

DR. CHILDRESS: Steve? Could we try to move on to do something about risk next.

MR. HOLTZMAN: Just an endorsement of what Alta said. That does happen on occasion, Alta. It goes to the further question of the form of the report. For it to be effective in giving our IRBs that kind of guidance, what is it about the way weíve written this thing thatóif you look at your question, it was are these rules clearly prescribed in the current draft. Weíve just spent 15 minutes trying in some measure to figure out what do we say and do we agree. That canít be very good guidance. So somehow we have to get a step back from whatís an enormous amount of important stuff thatís in here and say how do we put it into a format where, in fact, there will be a response to it.

DR. MORENO: Weíve already talked about an executive summary and introductory section that can boil the important points down. And it clear from what people have said that needs to be done.

DR. CHILDRESS: Weíll take Alex, and the perhaps we can move on to risk.

PROF. CAPRON: Alta, the only question I have about the description you gave was you said at one point the IRB would look at the person and decide is this a good person to play that role. I understand the that the thrust of what had been said is theyíre going to have an approval for a research project, there are patients at this institution, my understanding was, our hope was this would be the health care professional who is knowledgeable about that patient and in a therapeutic relationship with them who could maintain that therapeutic relationship and help advise and evaluate what the researcher is bringing in. Thatís going to be Dr. Jones here, Nurse Smith here, therapist so and so. Thereís not going to be one person. But if we look at the transcript, Alta, and we wrote down what youíve said, it would have been that they were approving a person. It seems to me what weíre talking about is a category of people which will include many potentially different professionals, some of whom may be milksop doctors who wonít stand up to their colleagues, and others of whom may be dynamite nurses who wonít let a doctor hurt a patient because theyíre holding a club over his head. Who knows what. But itís going to be a whole variety not defined by profession. Itís a category, right?

DR. DUMAS: Thatís what I thought Alta was saying.

PROF. CHARO: But for a given person itís a specific person.

PROF. CAPRON: But itís not a specific person, because the research protocols, for the most part, are going to say we want to recruit 20 patients with the following conditions, we donít know which ones are going to agree to be in, and who are going to have the conditions of this project. So which ones of the staff at this hospital or outside doctors who have seen them before?

PROF. CHARO: I suspect that unless we get even more specific, and remember, nothing that we suggest is going to be required absent a regulatory change, which wonít happen even if it did happen for ten years, so at best weíre talking guidelines, right? Unless we were to specify, I suspect there would be variable ways in which this kind of thing would be implemented, as is true for everything with IRBs. Some IRBs would ask that the protocol come in with a generic descriptor like we will use the primary care physician, or we will use the doctor who runs the ward, depending on the context. In other cases, IRBs would approve this conditional upon having for each recruited patient notification of who it is thatís going to be the independent monitor, and the IRB will not allow you to begin actual work with that subject until theyíve seen who the monitor is and theyíve had a chance to see whether or not it raises any red flags.

It will depend on exactly which IRB youíre working with, and they run the gamut. Now we could decide we want to get into that level of detail.

PROF. CAPRON: Donít we have any minimal floor here, Alta?

PROF. CHARO: I wasnít saying that as a challenge. We could decide if we want to get into that level of detail or not.

PROF. CAPRON: I understand that. This is a broader questionówhich Jim posed to one of our afternoon witnessesówhich is when we talk abut the IRB may, and the IRB may, present guidelines already allow IRBs to place all sorts of conditions that are way above the federal requirements, right?

PROF. CHARO: Right.

PROF. CAPRON: They can already insist that you have three independent doctors. The question is do we want to say that an IRB should not allow certain categories of research to go forward until it has ensured that a person with the following qualifications, as a minimum, shall be appointed to work with the potential subject in a therapeutic, protective, whatever role that they want to describe it as. Or, are we going to say this is something IRBs can pick out of the tool chest? Arenít we saying then, in fact, the NIH Common Rule should be modified in this regard to say that this is required that the IRBs ensure that such a person is in place.

PROF. CHARO: First, letís remember that this particular tool, the independent monitor, was never in our recommendations required for any category of research. It was always an optional addition for IRBs above and beyond even what the recommendations say should be the new regs, the theoretical new regs. It was never required. It was an additional ó

DR. CHILDRESS: Which are you talking about? Are you talking about in the past?

PROF. CHARO: Yes.

DR. CASSELL: Consent monitor is different.

PROF. CAPRON: Thatís not consent monitor. This is physician advisor.

DR. CHILDRESS: Right. But she was speaking about consent monitor.

PROF. CAPRON: Non-beneficial research.

PROF. CHARO: Oh, excuse me. Sorry. Okay. I confused myself for a moment. Right. Right. Right.

PROF. CAPRON: But this was just a generic question of which this is an example. Arenít we talking about here that one outcome, not ten years from now, but before research should go forward is that our report would come in, NIH would publish, take the report and put forward modifications in the regulations in a special subpart.

PROF. CHARO: You mean in 2010?

DR. CHILDRESS: I think theyíre to be offered as guidance.

PROF. CHARO: Even as guidance.

PROF. CAPRON: Guidance before that. But the objective is to say that there are minimum requirements.

DR. CHILDRESS: I would note that even in the recommendation part weíve revised this to say "should" not merely "may." The earlier draft had "may," "The IRB may consider...." And this one does actually change it. So it tried to strengthen that a little bit.

PROF. CHARO: But the minimum requirements youíre talking about are the minimum requirements for the professional, that it should be somebody with personal knowledge of the patient. Well, what minimal requirements are you talking about? Those?

PROF. CAPRON: The minimal requirement is that the IRB should ensure that it exists as opposed to the IRB might have such a primary care person involved in a certain category. Iím saying that the IRB should have. Itís just what Jim just said, IRBs should have. Then we could say conscientious IRBs will do it now, others will wait until the Federal Government tells them they really have to do it and they can stop thumbing their nose at NBAC.

DR. SHAPIRO: This latter statement I think is really quite important. The issue of how long it would take to make any change in the Common Rule take hold is speculative, but the evidence says a very long time. And we would aspire for changes to take place faster than that, that some IRBs, at least many, would listen to some of our advice or other advice. NIH, of course, could adopt its own rules any time governing itself.

DR. CHILDRESS: I think we may have said enough on all that to provide the kind of guidance to staff, Jonathan and Eric and others, to work this out.

DR. BRITO: Really itís more of a clarification. When I read the flowchart, and when Rhetaugh was making her comments, Iím reading this word "physician" here as the person representing the subject in the research. When I go back through the text, though, and Iím reading the description of independent physician advisor, Iím not reading that as the same. Are we talking about the same?

DR. MORENO: Same.

DR. BRITO: We are talking about the same.

DR. MORENO: Independent of the researchers.

DR. BRITO: Because that changes.... Nonbeneficial, nonbeneficial, greater minimal risk research, right?

DR. MORENO: Right. And it could be a non-physician primary care professional.

PROF. BACKLAR: Somebody tell me the page youíre on.

DR. BRITO: You have a chart you canít see and Iím comparing it to page 174, where itís discussing independent physician advisors.

DR. CHILDRESS: And you donít have the other chart that weíre talking about. It was handed out today. Okay, can we turn to question of risks and we have, this is chapter 4, also discussed in various places along the way in some detail. And we have Laurieís proposal. Everyone received a memorandum today in which she raised questions as she has before about our deletion of the category "minor increment over minimal risk." And sheís arguing for the three rather than the two categories.

DR. MORENO: Can I just speak to that, Jim? I think we addressed this last time. We are not, so that everybodyís on the same wavelength here, we are not eliminating anything. You can have as many categories above minimal risk as you like. And you can have as many categories below minimal risk as you like. Weíre only specifying in this draft the minimal, the minimum requirements if one is above that threshold of minimal risk. IRB can impose or apply, introduce whatever other protections it likes. So this is not eliminating a category. And the category as I understand it...

DR. CHILDRESS: Of particular concern is that we are eliminating it as a standard for classifying research protocol.

DR. MORENO: Youíre not.

DR. CHILDRESS: In our recommendation.

DR. MORENO: No, weíre not, though. Weíre eliminating it as a basis for developing incremental protections. We havenít seen a reasonable way to do that.

DR. DUMAS: I understand, and I like that.

DR. SHAPIRO: What do you like, Rhetaugh?

DR. DUMAS: I like the idea of designing protections according to minimum level of risk, whether itís minimum or whether itís above it. And that, to me, eliminates a lot of confusion on the gradations in between. Anything above minimum level is what weíre talking about protecting.

DR. CHILDRESS: Other discussion?

DR. BRITO: But I can also understand Laurieís concern because depending on the IRB, depending on how much time is spent, I could see how some research that is just that grade above minimal risk could be preventedósome beneficial research. So I can understand the concern. So I think maybe if we define it the way itís defined is fine, but maybe just a little bit more explanation somewhere in there about that it really needs to be looked at very carefully when there are just levels above minor or minimal risk, etc. Some gradation.

DR. DUMAS: Then you get into the distinctions with the variation among people on what they call "just above minimal risk."

DR. CHILDRESS: Alta, then Eric Meslin.

PROF. CHARO: I continue to believe that simpler is better in this area. And that an additional category with separate procedures for "minor increment over minimal risk" is an invitation to confusion at the IRBs. However, in light of Laurieís continued concern that the absence of this category is going to mean that there are a fair number of people who can no longer give informed consent, who will then become ineligible for important research that is a minor increment over minimal risk and nonbeneficial, Iíd like to suggest that this report go out to the public in a way that highlights that question for reactions from the public and particularly asks for some examples of the kind of research that would be affected and the magnitude of the research that would be lost. But as we continue to debate this particular issue, we will know exactly whatís at stake.

DR. MESLIN: Just very quickly. When the writing bucket, and this is for the benefit of the Commissioners who werenít participating in that conference call, discussed this issue, two points were raised that I think bear repeating. The first is that the issue is only relevant if the "minimal risk" bar is set at a particular place which either is overly inclusive or overly exclusive. The worry of the writing bucket was that if the bar for minimal risk is set so high that everyone would be in minimal-risk research and only incredibly risky research was above minimal risk, that would clearly be inappropriate because no one would be afforded protections. If, conversely, the bar was set so low that virtually anyone could jump over it and be therefore in a category of greater-than-minimal risk, that too would be worrisome. So the issue was where to set the level of minimal risk, which is a judgment call, and I think the writing bucket agreed that examples would be helpful.

The other point that the writing bucket discussed but doesnít come out in the report, except for an additional staff suggestion, was in the absence of any data or evidence that IRBs can make the distinction, the fine distinction, between slight increment over minimal, even greater slight increment over minimal, etc., that it would not be doing them a service to make those distinctions. And besides, the regs permit us to have these two levels anyway with the exception of the childrensí regs. So it was suggested that one prospective recommendation might be to evaluate this particular recommendation in the field after we implement it.

PROF. CHARO: But Eric, one thing in B response confuses me. We are not in control of the definition of minimal risk. It is a definition controlled by the regs.

DR. MESLIN: I understand. Well yes and no. We could .... I donít want to do the Larry worry, but the definition of minimal risk in the regs is sufficiently vague for purposes of this discussion; that we could have, the writing bucket could have that discussion and ask where the bar would be set. Eric Cassell asked whether we should be adding a new word to the minimal risk definition to include treatment, a particular type of treatment. So youíre right, we are limited by what the regs say, but the definition is flexible to have this point still be on the table.

PROF. CHARO: Okay.

DR. MESLIN: And we included the regs in everyoneís briefing book if you wanted to...

DR. CHILDRESS: Alex, just a suggestion to make sure we had a debate in clear form. Are there other thoughts on the question of risk?

DR. CASSELL: I hate to do it, but ...Trishís concern that risk is different to this population than it is to another population is really not addressed. And yet sheís correct about it. That something may seem like minimal risk to somebody else but to somebody in this population feel very risky. We havenít addressed that, and one way to address it was to try and just eliminate too many categories. But in fact we have not addressed that.

DR. CHILDRESS: But we have addressed it in the text, though, right?

DR. SHAPIRO: Yes.

DR. CHILDRESS: But not in the recommendations.

DR. SHAPIRO: Yes.

DR. CHILDRESS: Harold, sorry, Harold was first, sorry.

DR. SHAPIRO: The issue of what research is going to be discouraged by this approach as opposed to, let me just call it Laurieís approach... The issue of what research is going to be discouraged or what useful research we will no longer pursue because of having these two categories rather than three, as far as I can tell so far remains an assertion. And I would feel much better about this if we had something more than an assertion on this matter. Otherwise, I think the logic takes either the minimum versus not minimum. But there may be something real here, which I donít know about, and quite willing, even likely that thatís the case. But I really donít want to move that way; Iím happy with all the suggestions, wait for some feedback, but I wouldnít want to move that way without something beyond an assertion in this area. And perhaps get some data on this, I just donít know whatís available.

DR. CHILDRESS: Tom?

DR. MURRAY: It would seem to me that some progress was made in this discussion of the last several minutes, but itís not clear to me where we came out on it, and I wondered if anybody would be willing just to state where we think we are in terms of a shared agreement about this so we can come back to it next week in writing and have people say no, thatís not what we agreed to. Why donít we try to nail it now?

DR. CHILDRESS: Itís late in the day, we may not have many volunteers.

DR. SHAPIRO: The suggestion, the only actual suggestion I heard was Altaís suggestion, that namely we keep it in this form as it goes out for comment. But we find some way to encourage response on the issueóthat we focus attention on the issue here from other investigators, other people who know things, just what they feel on this issue. We know how Laurie feels, and sheís a thoughtful person, very experienced in this area. But letís hear from others. That was the suggestion that Alta made, which seemed entirely reasonable.

DR. MIIKE: Yes. If weíre going to have definitional problems of what is minimal risk, Iíd have an even greater definitional problem of what is a minor increment.

DR. SHAPIRO: I completely agree with that.

MR. HOLTZMAN: I assume we all agree with that because in the beginning was the action of the word, and what Laurie cares about here is the action here. The implication that no box...that says there is a class of research which will not be able to be done. So the issue is whether or not weíre going to, in terms of our simple bimodal classification, now change that to a yes or leave it as a no and look at the implications. We talked about an empirical question, that how much research should be excluded. I think the little interchange between you and Dr. Shore and myself really went to the point of what is the interpretation under the reg of what is minimal risk. And are we in a situation, in fact sociologically, where people are being broader in their interpretation of what is risk than they used to be. And so therefore the class of research that would be excluded under this proposal is in fact getting broader. If anything, I think those are the issues that are at stake. And I donít think we have the consensus on whether even going with the bimodal scheme should be a yes or a no.

DR. BRITO: Weíve previously had quite a discussion on defining minimal risk from experts and from within ourselves, etc. And no oneís been able to come up with a conclusion. At first I thought Altaís idea was a great idea putting this out for the public, but Iím not sure weíre going to end up coming to a conclusion with that either. The way the Federal regulations are written, theyíre written vaguely in this area and there must be a reason for that. And I think itís because past commissions havenít been able to define minimal risk. And I think thereís a lot of variation of what isóweíve talked about this beforeówhat is minimal risk to one may not be minimal risk to others, whether itís the investigator or the subjects in the research. What I was suggesting earlier is, and I donít know if I made myself clear, is that I think in the body of the text we discuss what Laurieís concerns are. And she gives one clear example of the PET scans etc. in her letter about what is just above minimal risk. But in our recommendations, we make it just the two categories where we make it very clear it is up to the IRB to determine what is greater than minimal risk, because that is in the end what weíre entrusting the IRBs to do to determine that. Iím not sure, I think weíre going to get such a varied response from putting this out.

DR. SHAPIRO: Well in the way I think about this, Arturo, itís hard to define "minimal risk."

DR. BRITO: Right.

DR. SHAPIRO: It doesnít get easier by defining "minor increment over minimal risk." It doesnít change anything. It just gives you some leeway to figure out what minimal is. Thatís all it does, itís just another way of defining minimal.

DR. BRITO: But shouldnít we leave it up to the IRB to define what is above?

DR. SHAPIRO: Well, my only point is you donít need two categories to leave it up to them. If youíre going to leave it up to them, you can leave it up to them in one category. Either itís minimal or itís not. And thatís just how I think about it. Iím not an experienced investigator in this area and maybe thereís something quite bad about that.

DR. CHILDRESS: Larry and Diane.

DR. MIIKE: I think the answer is whatever weíve been trying to do as a decisional pathways. The more decision points you give them, the more comfortable they would feel in erring on the side of caution because you still donít block it just by saying itís greater than minimal risk. You just have more safeguards built into the process.

PROF. SCOTT-JONES: Another problem that occurs when you have minimal risk and then minor increase over minimal risk is that minimal risk is defined in terms of an ordinary, everyday person. And then minor increase over minimal risk is defined in terms of the individual research participant, and then the logic is used to justify higher level of risk to that individual participant than you would to an everyday person who doesnít have the problems of that potential participant. And it is then used to justify even greater risk to the individual participant, and I think thatís a problem with using the two categories and defining them very, very differently from one another.

DR. CHILDRESS: That discussion is on 92 in the text.

PROF. SCOTT-JONES: Right, on 92 and 93.

DR. CHILDRESS: Okay, I have Bette and then David.

MS. KRAMER: Itís late in the day, but it seems to me that maybe where the problem lies is in trying to define specific procedures as minimal risk or greater minimal risk, when in fact it depends on the context. So would it be possible to incorporate in the report that to capture that notion, citing for instance, Laurieís concern that this certain population not be automatically excluded by the use of a procedure that might in some context be considered greater than minimal risk; but then for people of another context, could possibly render great knowledge. I donít know if that just confuses it more.

DR. COX: That was going to be my point. I mean we have something here, we have a distinction we want to make as an example. We donít make a whole new class. Make the class, which weíre talking about and put in the distinctions, saying that by doing this we donít want to screw up and turn this into a complicated deal. I think hereís one example of something you donít want to shut down. So you could just use this as an example and you donít have to make a whole new class about it. So I do agree with Bette.

DR. CHILDRESS: Alex, Jonathan, and Rhetaugh.

PROF. CAPRON: I have two points. One is I agree with the notion of staying with the minimal risk definition and then flagging for public response examples of research that would become problematic. Not forbidden, but potentially delayed and made more difficult under our charter. The problem I have is in reading the present sections on page 90 to page 100 based, I canít figure out what weíre saying, because we mix two...to follow up on Dianeís point, we mix two different issues. One is the question which was addressed by the national commission and then dropped in the language of the regulations. And we heard from Gary Ellis a while ago, very interesting discussion of that history and how OPRR looks at it now, which I donít think actually merges that clearly. I think we can go back to the transcript and get that position more clearly stated. Which is whether or not the bar is set by reference to things in the lives of people who have the diseases under study or the general population. That overlaid onto that is the observation that any particular procedure may be of higher or lower risk, particularly in terms of psychological reaction, for people who are in this special population than for people in the general population. As Bette said, that would be relevant if we were saying PET scanning or venous punctures or spinal taps are or are not on one side of the line. You have to say wait a second, something thatís okay for you is not okay for someone else in this other category. So, but thatís not really what this is about. This is about how you define that reference group, and then you may come back to the reference group and say, now when we evaluated a particular procedure, letís keep this other insight in mind that the IRB should ask investigators and ask non-investigators or experts on the population, are they going to react differently? Is there some reason why this is lower risk for them because theyíre so familiar with it, or higher risk because theyíre more disturbed by this? And this discussion, I donít know where we come out. If you look at the top of page 100, it sounds as though weíre getting to our point. "For persons with mental disorders that may affect decisionmaking capacity, the risks that are minimal for general population may pose special psychological burdens, even with regard to interventions the person may be familiar with," and so forth, and we just ... it sort of peters out. I expected us to finally tell us that we expect people to use the general population standard or the specific population standard. I would like to know where we come out on that. Because otherwise our whole notion that weíre setting a bar and saying if youíre over that bar, particular requirements click in doesnít mean anything.

DR. CHILDRESS: Okay, I have Jonathan, Rhetaugh, Diane, Alta, and Eric.

DR. SHAPIRO: Just after that long list is announced, we have about ten minutes, okay, before we have to turn to Tom. Weíll take a half hour more tomorrow to try and ...

DR. MORENO: Briefly, we do have a box on the graph for exactly the contextualization of risks that you guys are talking about. And it is supposed to fall in this box that reads IRBs assess the investigatorís determination of risk in light of the specific subject population, does this risk involve greater than minimal risk. And itís addressed in the recommendations in 171-172. But I agree with Alex that we need to indicate exactly where we come down on this earlier in the text, in the dicta portion and not only in the recommendations.

DR. DUMAS: Am I next? The concern that I have is not that we are eliminating anybody from the possibility of participating in the research. What we are doing is only classifying those people who need additional protections. And I would rather err on the side of more protections than fewer.

DR. CHILDRESS: Alta?

PROF. CHARO: I share Rhetaughís presumptive directions. I know thatís exactly where this source of disagreement is with Laurie. Perhaps for the agenda for tomorrow, I think itís possible that we would be well served if in conjunction with this report we were to try and produce a document as short as the Belmont Report and as influential for the ages, which focuses a little bit less on some of these details and little bit more on the thrust of why these details are being fought over. Such as, the coalescence of factors that leads to special vulnerability, the presumption in favor of excess protection at the risk of losing certain areas of research rather than in favor of research at the risk of exploitation, and why that particular presumption is being chosen. And examples of these tools with a focus on their purpose as much as their operation, including the retention of a minimal risk category thatís defined by reference to the Federal regs, which do in fact talk about a general population that is an average of healthy and ill, which is one of the reasons why it is so difficult to understand because it includes both in its own existing interpretations. But that very deliberately does not try to redefine minimal risk by definition with this subject population. The only purpose for doing that, of course, would be to expand the number of people who can be researched upon without consent, without giving their own consent. And thatís not our thrust. But if we were to try to produce something really short that highlighted the underlying goals, that might be a very important part, a most important part, of all of this exercise. Just one last thing in defense of staff, one of the reasons why this has gotten to be a hundred and so odd pages is that every minor thing that any of us ever mentioned as being of interest has now been incorporated. So we are collectively responsible for how difficult it is to find the salient points.

DR. CHILDRESS: In some ways, it seems to me, you may be proposing a special executive summary, that is, a document that really says why this is very important, not quite an executive summary.

PROF. CHARO: Itís not exactly an executive summary.

DR. CHILDRESS: But itís something that will play that kind of role. Diane?

DR. SCOTT-JONES: I just wanted to say that now that Jonathan has pointed out what the flowchart says, it does put this in a different light. But I would really strongly urge what Alex has said, that we do need to clean up the language in the text, or it is very, very confusing. And then also, I read really carefully what Laurie has said, and I know that she said that many times before, and I think that somehow we ought to acknowledge her position. If we agree ... if the rest of the Commission decides differently than Laurieís position, I think we really should acknowledge her strongly-held views.

DR. CHILDRESS: Anyone has a right to file a dissent if we end up ever finishing a report. It would be possible to have a dissent. Chair, weíre at 5:15.

DR. SHAPIRO: Okay, thank you.

PROF. CAPRON: I just urge that if weíre comfortable with the current Federal position which as I said, Alta, I believe Gary told us very nicely to just go back to the transcript, then we ought to have that in place of the discussion page 90 to 100 and just say, "Minimal risk means the present thing," and then maybe a footnote explaining the Canadian trial and the this and the that and all the different groups that have talked about it. And then come to this question which is the assessment of the risks of this research are compared against that metric.

PROF. CHARO: Right. And then emphasize again that IRBs are always welcome to say that although the research is generally considered minimal risk, to this research population itís not and we are choosing to treat it as nonminimal. That is always within their purview.

PROF. CAPRON: Exactly, but thatís the standard.

DR. SHAPIRO: Okay. Jim has a comment. I want to make a comment, and Tom will be back and give us instructions.

DR. CHILDRESS: I notice that we have a few items left over for tomorrow. Harold said we could have about 30 minutes tomorrow. I think some of these wonít take us very long. I would note in addition to the report here that Laurie also raised a question about our requirement of necessity to look at that as well. And then Trish has raised issues and a question about whether we have adequately dealt here with the question of conflict of interest. We sort of mentioned it several times in passing, and itís implicit in some of the recommendations we make that what weíre trying to do is really avoid conflict of interests, but we need to be more specific about that.

DR. SHAPIRO: Thank you. Iím going to turn to Tom in just a minute. With respect to the comment not that Jim made but the discussion that ended with Alexís comment, that is are we satisfied or do we get to be satisfied with the Federal regulation, which as Alta described as some kind of average, that may be a good to start. That bothered me a little bit when I went through this, frankly, and I tried to come to a formulation in my own mind which said something like the following, and I donít have this well articulated yet, but just give you the notion maybe we can talk about it tomorrow or another time: that we did allow ourselves to look specially at this population, but never and whatever we adopted would never exceed the Federal regulations, that is, you can only go away from the Federal regulations and that is to be more protective. And I was trying to formulate that effectively and I never really quite succeeded, but maybe somebody here might think about how we could formulate that and if itís a good idea altogether. So that eliminated the possibility that you would exploit this population by defining something which allowed greater leeway. But you would allow yourself to move in the other direction. That may or may not be a useful thing to think about, we can come back to that. There are two other tools which I came away with after reading this report, thinking that might be very useful in this area which we donít seem to ever discuss; as far as I can see others donít discuss it either. And I just want to mention them here. Iíve already mentioned it to Jim earlier today, and I mentioned it not to cause any discussion nowówe donít have timeóbut to see if any of you might think about this and we could review it another time whether theyíre useful or not. The two tools I have in mind are audit and disclosure. In all these areas where weíre struggling, whether IRBs are overworked or not overworked or whether we can define a regulation or not define a regulation, whether we want all IRBs to have the same rule or and so on, a lot of those, it seems to me, could be at least resolved in some respect either by a disclosure document where the IRB just indicated what it does and published it and people could look at it, and thatís a certain amount of accountability. And/or whether audit of IRB procedures is something thatís appropriate for us to consider. Not to audit every IRB every year, but whether IRBs on some basis might be subject to audit just to see how things are going. Because time and time and again weíve come up with the issue that weíre not quite sure just how the IRBs are doing and what theyíre doing. And it seems to me that those are two tools which may or may not be appropriate. Iíve not thought about it carefully enough, but they arenít used and are very widely used in other contexts for exactly this purpose. And so thatís something I would just ask the Commissioners to think about as to whether that is even any conceivable way that those tools might be useful and simplified. The purpose would be to simplify yet sustain the effectiveness of what weíre proposing. If it complicates it, Iím not so sure we want to think about it very long. So thatís just something to think about, but let me now try to adjourn the meeting by turning to Tom to give us some instructions and then itís tomorrow morning, what time do we convene? Eight oíclock tomorrow morning. Tom?

PROF. BACKLAR: Are you going to start with this in the morning?

DR. SHAPIRO: Yes, weíre going to start with this.

DR. MURRAY: [Administrative details].

PROF. BACKLAR: If Jim has any time to call me this evening, heís welcome.

DR. CHILDRESS: Iíll call you.

[End of discussions of Day 1)